U.S. patent number 4,584,288 [Application Number 06/692,489] was granted by the patent office on 1986-04-22 for 6,6-eth ylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolactones, processes for the production thereof, and pharmaceutical preparations containing them.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Sybille Beier, Dieter Bittler, Walter Elger, Henry Laurent, Klaus Nickish, Rudolf Wiechert.
United States Patent |
4,584,288 |
Nickish , et al. |
April 22, 1986 |
6,6-eth
ylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolactones,
processes for the production thereof, and pharmaceutical
preparations containing them
Abstract
6,6-ethylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17.alpha.-carbo
lactones of general Formula I ##STR1## wherein ##STR2## is a
CC-single of CC-double bond, R.sub.1 is a hydrogen atom or a methyl
group, R.sub.2 is a methyl or ethyl group, and ##STR3## exhibit
strong gestagen potency and an aldosterone-antagonistic
activity.
Inventors: |
Nickish; Klaus (Berlin,
DE), Bittler; Dieter (Berlin, DE), Laurent;
Henry (Berlin, DE), Wiechert; Rudolf (Berlin,
DE), Beier; Sybille (Berlin, DE), Elger;
Walter (Berlin, DE) |
Assignee: |
Schering Aktiengesellschaft
(Berlin and Bergkamen, DE)
|
Family
ID: |
6225757 |
Appl.
No.: |
06/692,489 |
Filed: |
January 18, 1985 |
Foreign Application Priority Data
|
|
|
|
|
Jan 20, 1984 [DE] |
|
|
3402329 |
|
Current U.S.
Class: |
514/172; 540/11;
540/44; 540/8; 540/15 |
Current CPC
Class: |
A61P
5/38 (20180101); C07J 53/008 (20130101); C07J
21/006 (20130101); C07J 1/0059 (20130101) |
Current International
Class: |
C07J
1/00 (20060101); C07J 53/00 (20060101); C07J
21/00 (20060101); C07J 019/00 (); A61K
031/58 () |
Field of
Search: |
;260/239.57
;514/172 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Roberts; Elbert L.
Attorney, Agent or Firm: Millen & White
Claims
What is claimed is:
1. A
6,6-Ethylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolacton
e of the formula ##STR9## wherein ##STR10## is a CC-single or
CC-double bond, R.sub.1 is hydrogen or methyl,
R.sub.2 is methyl or ethyl, and ##STR11##
2. A compound of claim 1 wherein ##STR12## is a CC-single bond.
3. A compound of claim 1 wherein ##STR13## is a CC-double bond.
4. A compound of claim 1 wherein R.sub.1 is H.
5. A compound of claim 1 wherein R.sub.1 is CH.sub.3.
6. 6,6-Ethylene-15.beta.,16.beta.-methylene-3-oxo-17.
alpha.-pregn-4-ene-21,17-carbolactone, a compound of claim 1.
7. 6,6-Ethylene-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-p
regna-1,4-diene-21,17-carbolactone, a compound of claim 1.
8. 6,6-Ethylene-15.alpha.,16.alpha.-methylene-3-oxo-17.alp
ha.-pregn-4-ene-21,17-carbolactone, a compound of claim 1.
9. 6,6-Ethylene-15.alpha.,16.alpha.-methylene-3-oxo-17.alp
ha.-pregn-1,4-diene-21,17-carbolactone, a compound of claim 1.
10. 6,6,-Ethylene-18-methyl-15.beta.,16.beta.-methylene-3-oxo-
19-nor-17.alpha.-pregn-4-ene-21,17-carbolactone, a compound of
claim 1.
11.
6,6,-Ethylene-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-pregn-
4-ene-21,17-carbolactone, a compound of claim 1.
12. A pharmaceutical composition comprising an amount of a compound
of claim 1 and a pharmacologically acceptable carrier.
13. A composition of claim 12 further comprising a contraceptually
effective amount of an estrogen.
14. A composition of claim 12 wherein the amount of said compound
is 0.5 to 5 mg.
15. A method of achieving a contraceptive effect in a patient
comprising administering an effective amount of a compound of claim
1 to the patient.
16. A method of claim 15 further comprising administering an
effective amount of an estrogen to the patient.
17. A method of achieving an aldosterone-antagonistic effect and a
gestagenic effect in a patient comprising administering an
effective amount of a compound of claim 1 to the patient.
18. A compound of the formula ##STR14## wherein R.sub.1 is H or
CH.sub.3,
R.sub.2 is CH.sub.3 or C.sub.2 H.sub.5, and ##STR15##
Description
BACKGROUND OF THE INVENTION
This invention relates to
6,6-ethylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolacton
es, processes for the production thereof, and pharmaceutical
preparations containing them.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds having
valuable pharmacological properties.
Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
These objects have been achieved by providing
6,6-ethylene-15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolacton
es of Formula I ##STR4## wherein ##STR5## is a CC-single or
CC-double bond, R.sub.1 is a hydrogen atom or a methyl group,
R.sub.2 is a methyl or ethyl group, and ##STR6##
DETAILED DISCUSSION
The novel compounds of Formula I have, besides a high
aldosterone-antagonistic activity, a strong gestagen potency. The
combination of aldosterone-antagonistic and gestagen activities is
not found in any of the known synthetic gestagens of the
ethynylnortestosterone or hydroxyprogesterone series, but it does
exist in the natural gestagen, namely progesterone. Since the novel
compounds possess the progesterone-like profile of activity, they
will not cause, when used as contraceptives, the otherwise
occurring side effects, such as increases in blood pressure and
edemas.
By replacing the ethylene group in the 6-position by a
6.beta.,7.beta.-methylene group, compounds are obtained which
likewise show aldosterone-antagonistic and gestagen effects, but
wherein the gestagen activity is not so strongly pronounced (DOS
No. 3,022,337).
In a test for antialdosterone activity, the novel compounds of
Formula I have proven to be up to five times more effective than
spironolactone.
In the modified Clauberg test for gestagen activity, positive
results are achieved with quantities of 0.03 mg of the compounds of
this invention upon subcutaneous administration.
In the pregnancy-maintaining test on rats and mice, the minimum
amount required for attaining a positive effect ranges around 0.1
mg.
The novel compounds of Formula I can be utilized by themselves or
in combination with estrogens in preparations for contraception in
fully conventional fashion, e.g., analogous to the use of
conventional gestagens in these contraceptive preparations.
According to this invention, the novel compounds are to be used
particularly by women desiring contraception and prone to
hypertension on account of risk factors present, such as advanced
age, obesity, or smoking. Considering the profile of these
compounds which is comparable to that of natural progesterone, they
are apt to improve well-being and compatibility over conventional
preparations even in women who cannot be classified as hish-risk
patients. The dosage of the compounds of this invention on
contraceptive preparations is to be preferably 0.5-5 mg per day.
The gestagen and estrogen active agent components are administered
in contraceptive preparations preferably orally in combination. The
daily dose is administered preferably all at once as usual. The
estrogen is administered daily in a quantity corresponding to that
of 0.03-0.05 mg of ethynylestradiol.
The novel compounds of general Formula I can also be utilized in
preparations for the treatment of gynecological disorders. Because
of their favorable activity profile, the compounds of this
invention are especially well suited for the treatment of
premenstrual complaints, such as headaches, depressive moods, water
retention, and mastodynia. The daily dose when treating
premenstrual difficulties is about 1-20 mg, e.g., analogously to
Duoluton.RTM.. They can also be used, analogously to spironalactone
as diuretics and antihypertensives in the same dosis range as
spironolactone.
The pharmaceutical preparations based on the novel compounds are
formulated conventionally by processing the active agent,
optionally in combination with an estrogen for contraception, with
the excipients, diluents, if desired flavoring agents, etc.,
customary in galenic pharmacy, and converting this preparation into
the desired form of administration. Tablets, dragees, capsules,
pills, suspensions, or solutions are especially suitable for the
preferred oral administration. Particularly suited for parenteral
administration are oily solutions, e.g. solutions in sesame oil,
castor oil, and cottonseed oil. To enhance solubility, solubilizers
can be added, such as, for example, benzyl benzoate or benzyl
alcohol.
Suitable hosts include mammals, including humans.
The compounds of this invention according to general Formula I can
be prepared by conventionally introducing a 6.alpha.-hydroxy-methyl
group into
15,16-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolactones of
general Formula II ##STR7## wherein ##STR8## R.sub.1 and R.sub.2
are as defined for Formula I, by way of the 3,5-diene-3-amines
using formalin, followed by reconstitution of the 4-ene-3-oxo
system forming the 6-methylene compound from the
6.alpha.-hydroxymethyl compound. and methyenating this 6-methylene
compound to the 6,6-ethylene compound, and optionally introducing
the .DELTA..sup.1 -double bond.
First of all, the .DELTA..sup.4 -3-ketone is converted, with a
secondary base, into the corresponding .DELTA..sup.3,5 -3-amine.
Suitable secondary bases are, for example, diethylamine, aniline,
pyrrolidine, and morpholine.
For the introduction of the 6.alpha.-hydroxymethyl group, the
.DELTA..sup.3,5 -3-amine is treated with formalin in an alcoholic
solution (Helv. Chim. Acta 56 (1973) 2396).
Water is split off from the 6.alpha.-hydroxymethyl compound with
hydrochloric acid in dioxane, to obtain the corresponding
6-methylene compound. The water cleavage can also be performed by
first introducing a fugacious group and splitting it off again.
Suitable fugacious groups are, for example, mesylate, tosylate, and
benzoate.
The methylenation of the 6-methylene compound to form the
6,6-ethylene compound can be effected in dimethylsulfoxonium
methylide. For this purpose, the 6-methylene steroid is added to a
suspension of trimethylsulfoxonium iodide with sodium hydride in
mineral oil and dimethyl sulfoxide, or to a solution of
trimethylsulfoxonium iodide and sodium hydroxide in dimethyl
sulfoxide. The reaction is finished after 15-60 minutes at
20.degree.-40.degree. C. Corresponding reactions are described in
J. Am. Chem. Soc. 84 (1962) 866-868.
The optionally following introduction of the .DELTA..sup.1 -double
bond is conducted according to methods known per se and can be done
by chemical or microbiological processes. Suitable chemical
dehydrogenating agents include, for example, selenium dioxde,
2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium
triacetate, or lead tetraacetate. Suitable microorganisms for the
1,2-dehydrogenation include, for example, Schizomycetes, especially
those of the genera Arthobacter, e.g. A. simplex (ATCC 6946);
Bacillus, such as, for example, B.lentus (ATCC 13805) and B.
sphaericus (ATCC 7055); Pseudomonas, e.g. P. aeruginosa (IFO 3505);
Flavobacterium, e.g. F. flavescens (IFO 3058); Lactobacillus, e.g.,
L. brevis (IFO 3345); and Nocardia, e.g. N. opaca (ATCC 4276).
The 1,2-dehydrogenation is preferably performed chemically. For
this purpose, the 1,2-dihydro steroid is heated for a rather long
time in a suitable solvent with the dehydrogenating agent. Suitable
solvents include, for example, dioxane, tert-butanol,
tetrahydrofuran, toluene, benzene and/or mixtures of these
solvents. The reaction is finished after several hours. It is
recommended to control the conversion by thin-layer chromatography.
The reaction mixture is worked up once the starting material has
been converted.
The starting materials of Formula II are all known or readily
preparable from known starting materials using conventional
reactions, e.g., analogously to the preparations reported in
Examples 5 and 6 below.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever. In the following examples, all temperatures are set
forth uncorrected in degrees Celsius. unless otherwise indicated,
all parts and percentages are by weight.
EXAMPLE 1
(a) A solution of 4.1 g of
15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolactone
in 31 ml of methanol is heated under reflux with 2.05 ml of
pyrrolidine for 15 minutes. After cooling in an ice bath, the
thus-formed precipitate is suctioned off, washed with a small
amount of methanol, and dried, thus obtaining 4.5 g of
15.beta.,16.beta.-methylene-3-pyrrolidino-17.alpha.-pregna-3,5-diene-21,17
-carbolactone, mp 234.degree.-237.degree. C. (with
decomposition).
UV: .epsilon..sub.276 =22,900.
(b) At room temperature, 4.5 ml of 37% strength formalin solution
is added dropwise within 5 minutes to a solution of 4.5 g of
15.beta.,16.beta.-methylene-3-pyrrolidino-17.alpha.-pregna-3,5-diene-21,17
-carbolactone in 90 ml of ethanol and 45 ml of benzene. After a
reaction period of 30 minutes, the reaction solution is evaporated
to dryness under vacuum. The residue is chromatographed on silica
gel, thus producing 3.15 g of
6.alpha.-hydroxymethyl-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4
-ene-21,17-carbolactone as an oil.
UV: .epsilon..sub.241 =14,500.
(c) At room temperature, 3.15 g of
6.alpha.-hydroxymethyl-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4
-ene-21,17-carbolactone is agitated for 2 hours in 77 ml of dioxane
with 9.1 ml of 5N hydrochloric acid. The reaction solution is then
combined with an excess of sodium bicarbonate, filtered off from
the precipitated inorganic salts; the filtrate is diluted with
ether and washed with water. After drying and evaporation, the
residue is chromatographed on silica gel. Recrystallization from
diisopropyl ether/acetone yields 1.2 g of
6;15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolac
tone, mp 173.1.degree. C.
UV: .epsilon..sub.261 =11,300.
(d) At room temperature, 1.41 g of trimethylsulfoxonium iodide is
agitated for 1.5 hours with 239 mg of sodium hydride (55% oil
suspension) in 21.5 ml of dimethyl sulfoxide (DMSO). Under argon,
1.14 g of
6;15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolac
tone is added to this solution, and the latter is stirred for 50
minutes at room temperature. The reaction solution is then stirred
into ice water, weakly acidified with 2N sulfuric acid; the
thus-formed precipitate is filtered off and taken up in methylene
chloride. After drying and evaporation, the residue is
chromatographed on silica gel. Recrystallization from diisopropyl
ether/acetone yields 725 mg of
6,6-ethylene-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17
-carbolactone, mp 184.2.degree. C.
UV: .epsilon..sub.248 =14,150.
EXAMPLE 2
A solution of 670 mg of
6,6-ethylene-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17
-carbolactone and 670 mg of 2,3-dichloro-5,6-dicyano-p-benzoquinone
in 13.4 ml of toluene is stirred for 5 hours at 100.degree. C. The
reaction solution is then diluted with ether, washed with water,
sodium bicarbonate solution and water, dried, and evaporated. The
residue is then chromatographed on silica gel. After
recrystallization from diisopropyl ether/acetone, 445 mg of
6,6-ethylene-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-diene-
21,17-carbolactone is obtained, mp 199.7.degree. C.
UV: .epsilon..sub.243 =15,150.
EXAMPLE 3
(a) As described in Example 1, 5.9 g of
15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbolacto
ne is reacted in 40 ml of methanol with 2.95 ml of pyrrolidine and
worked up, thus obtaining 5.9 g of
15.alpha.,16.alpha.-methylene-3-pyrrolidino-17.alpha.-pregna-3,5-diene-21,
17-carbolactone, mp 235.degree.-237.5.degree. C. (with
decomposition).
UV: .epsilon..sub.276 =23,300.
(b) As described in Example 1, 5.9 g of
15.alpha.,16.alpha.-methylene-3-pyrrolidino-17.alpha.-pregna-3,5-diene-21,
17-carbolactone is reacted in 118 ml of ethanol and 59 ml of
benzene with 5.9 ml of 37% formalin solution and worked up,
yielding 3.7 g of
6.alpha.-hydroxymethyl-15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregn
-4-ene-21,17-carbolactone.
(c) 3.7 g of
6.alpha.-hydroxymethyl-15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregn
-4-ene-21,17-carbolactone is agitated in 90.5 ml of dioxane with
10.7 ml of 5N hydrochloric acid for 3.5 hours at room temperature.
The mixture is then worked up and purified as described in Example
1. After recrystallization from diisopropyl ether/acetone, 2.26 g
of
6;15.alpha.,16.alpha.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbol
actone is obtained, mp 162.5.degree.-163.5.degree. C.
UV: .epsilon..sub.262 =11,300.
(d) 1.87 g of
6;15.alpha.,16.alpha.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-21,17-carbol
actone is reacted, as described in Example 1, in 35 ml of DMSO with
2.31 g of trimethylsulfoxonium iodide and 393 mg of sodium hydride
(55% oil suspension) and worked up. Recrystallization from
diisopropyl ether/acetone yields 1.1 g of
6,6-ethylene-15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,
17-carbolactone, mp 176.6.degree. C.
UV: .epsilon..sub.247 =13,900.
EXAMPLE 4
At 80.degree. C., 600 mg of
6,6-ethylene-15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregn-4-ene-21,
17-carbolactone is stirred in 12 ml of toluene with 600 mg of
2,3-dichloro-5,6-dicyano-p-benzoquinone for 17 hours. The mixture
is then worked up and purified as set forth in Example 3, thus
obtaining 520 mg of
6,6-ethylene-15.alpha.,16.alpha.-methylene-3-oxo-17.alpha.-pregna-1,4-dien
e-21,17-carbolactone as an oil.
UV: .epsilon..sub.242 =14,600.
EXAMPLE 5
(a) As described in Example 1, 5.0 g of
18-methyl-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-pregn-4-ene-2
1,17-carbolactone is reacted in 125 ml of methanol with 2.5 ml of
pyrrolidine and worked up. Yield: 5.0 g of
18-methyl-15.beta.,16.beta.-methylene-3-pyrrolidino-19-nor-17.alpha.-pregn
a-3,5-diene-21,17-carbolactone.
(b) As described in Example 1, 5.0 g of
18-methyl-15.beta.,16.beta.-methylene-3-pyrrolidino-19-nor-17.alpha.-pregn
a-3,5-diene-21,17-carbolactone is reacted in 100 ml of ethanol and
50 ml of benzene with 5 ml of 37% formalin solution and worked up,
thus obtaining 2.33 g of
6.alpha.-hydroxymethyl-18-methyl-15.beta.,16.beta.-methylene-19-nor-17.alp
ha.-pregn-4-ene-21,17-carbolactone as an oil.
UV: .epsilon..sub.239 =13,200.
(c) At room temperature, 372 mg of
6.alpha.-hydroxymethyl-18-methyl-15.beta.,16.beta.-methylene-19-nor-17.alp
ha.-pregn-4-ene-21,17-carbolactone is stirred for 17 hours in 3.7
ml of pyridine with 572 mg of p-toluenesulfonic acid chloride. Then
0.09 ml of water is added, the mixture is further stirred for one
hour at room temperature, and the reaction solution is stirred into
ice water. The thus-formed precipitate is filtered off, washed with
water, and taken up in methylene chloride. After drying and
evaporation, 465 mg of
18-methyl-15.beta.,16.beta.-methylene-6.alpha.-tosyloxymethyl-19-nor-17.al
pha.-pregn-4-ene-21,17-carbolactone is obtained as an oil.
UV: .epsilon..sub.226 =20,600.
(d) A solution of 426 mg of trimethylsulfoxonium iodide in 15 ml of
DMSO is combined with 72 mg of sodium hydride (55% oil suspension)
and agitated for one hour at room temperature. Then, under argon,
300 mg of
18-methyl-15.beta.,16.beta.-methylene-6.alpha.-tosyloxymethyl-19-nor-17.al
pha.-pregn-4-ene-21,17-carbolactone is added to this solution, the
latter is stirred for another 15 minutes, and precipitated into ice
water. The precipitate is filtered off, taken up in ether, washed
with water, dried, and evaporated. Preparative thin-layer
chromatography yields 145 mg of
6,6-ethylene-18-methyl-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-
pregn-4-ene-21,17-carbolactone, mp 165.4.degree. C.
UV: .epsilon..sub.247 =14,650.
The starting compound according to 5(a) is prepared as follows:
A solution of 102 g of
15.alpha.-hydroxy-18-methyl-4-estrene-3,17-dione in 500 ml of
pyridine is combined under ice cooling with 50.9 ml of benzoyl
chloride and stirred for one hour under cooling. Then 9 ml of water
is added dropwise and the mixture is stirred for another hour. The
reaction solution is then stirred into ice water, the thus-formed
precipitate is suctioned off, washed with water, and dried, thus
obtaining 146 g of crude
15.alpha.-benzoyloxy-18-methyl-4-estrene-3,17-dione.
A solution of 146 g of
15.alpha.-benzoyloxy-18-methyl-4-estrene-3,17-dione in 1.46 l of
dichloromethane is combined with 441 ml of ethylene glycol, 294 ml
of orthoformic acid triethyl ester, and 7.3 g of p-toluenesulfonic
acid and stirred for 1 hour at 50.degree. C. Then, 20 ml of
pyridine is added, the mixture is diluted with ether and washed
with water. After drying and evaporation, 165 g of crude
15.alpha.-benzoyloxy-3,3-ethylenedioxy-18-methyl-5- or
-5(10)-estren-17-one is obtained.
A solution of 320 g of trimethylsulfoxonium iodide in 1.5 l of DMSO
is combined with 56.3 g of pulverized sodium hydroxide, and the
mixture is stirred for 2.5 hours at room temperature. Under water
cooling, 165 g of
15.alpha.-benzoyloxy-3,3-ethylenedioxy-18-methyl-5- or
-5(10)-estren-17-one in 300 ml of DMSO is then added thereto and
the mixture is stirred for 45 minutes. The reaction solution is
then stirred into ice water, the thus-produced precipitate is
filtered off, taken up in ether, washed with water, and dried. The
residue obtained after evaporation is chromatographed on silica
gel, yielding 79.2 g of
3,3-ethylenedioxy-18-methyl-15.beta.,16.beta.-methylene-5- or
-5(10)-estren-17-one as an oil.
A solution of 62 g of
3,3-ethylenedioxy-18-methyl-15.beta.,16.beta.-methylene-5- or
-5(10)-estren-17-one in 600 ml of absolute tetrahydrofuran (THF) is
cooled to -10.degree. C.; then, under argon, 186 g of potassium
ethylate is added and thereafter 124 ml of distilled propargyl
alcohol is added dropwise. The reaction solution is further
agitated under cooling for 45 hours and then stirred into ice
water, acidified with dilute sulfuric acid, and extracted with
dichloromethane. After drying and evaporation, the residue is
chromatographed on silica gel, thus obtaining 23 g of
3,3-ethylenedioxy-17.alpha.-(3-hydroxy-1-propynyl)-18-methyl-15.beta.,16.b
eta.-methylene-5- or -5(10)-estren-17.beta.-ol as an oil.
A solution is prepared from 23 g of
3,3-ethylenedioxy-17.alpha.-(3-hydroxy-1-propynyl)-18-methyl-15.beta.,16.b
eta.-methylene-5- or -5(10)-estren-17.beta.-ol in 150 ml of
2-propanol and 150 ml of THF and hydrogenated with hydrogen in the
presence of 23 g of Raney nickel catalyst. The mixture is then
filtered off from the catalyst and the filtrate evaporated to
dryness. As the residue, 23 g of crude
3,3-ethylenedioxy-17.alpha.-(3-hydroxypropyl)-18-methyl-15.beta.,16.beta.-
methylene-5- or -5(10)-estren-17.beta.-ol is obtained in the form
of an oil.
23 g of
3,3-ethylenedioxy-17.alpha.-(3-hydroxypropyl)-18-methyl-15.beta.,16.beta.-
methylene-5- or -5(10)-estren-17.beta.-ol is stirred in 230 ml of
dimethylformamide (DMF) with 69 g of pyridinium dichromate for 24
hours at room temperature. The reaction solution is then stirred
into ethyl acetate, suctioned off from the precipitated chromium
salts, and the filtrate is washed with water. After evaporation,
the residue is chromatographed on silica gel, yielding 15 g of
3,3-ethylenedioxy-18-methyl-15.beta.,16.beta.-methylene-19-nor-17.alpha.-p
regn-5- or -5(10)-ene-21,17-carbolactone as an oil.
15 g of
3,3-ethylenedioxy-18-methyl-15.beta.,16.beta.-methylene-19-nor-17.alpha.-p
regn-5- or -5(10)-ene-21,17-carbolactone is agitated for 6 hours at
room temperature in 150 ml of methanol with 15 ml of 8 vol-%
sulfuric acid. The reaction solution is then diluted with ether,
washed with water, dried, and evaporated. The residue is
chromatographed on silica gel and, after recrystallizing from
diisopropyl ether/acetone, 8.5 g of
18-methyl-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-pregn-6-ene-2
1,17-carbolactone is obtained, mp 202.5.degree.-205.5.degree.
C.
UV: .epsilon..sub.240 =17,400.
EXAMPLE 6
(a) A solution of 4.0 g of
15.beta.,16.beta.-methylene-19-nor-3-oxo-17.alpha.-pregn-4-ene-21,17-carbo
lactone in 35 ml of boiling methanol is combined with 2 ml of
pyrrolidine and heated for another 20 minutes under reflux. After
cooling, the thus-formed precipitate is suctioned off and washed
with a small amount of cold methanol and dried under vacuum,
yielding 4.3 g of
15.beta.,16.beta.-methylene-19-nor-3-pyrrolidino-17.alpha.-pregna-3,5-dien
e-21,17-carbolactone.
(b) 4.3 ml of formalin solution is added dropwise to a solution of
4.3 g of
15.beta.,16.beta.-methylene-3-pyrrolidino-19-nor-17.alpha.-pregna-3,5-dien
e-21,17-carbolactone in 43.6 ml of benzene and 87.2 ml of ethanol;
the mixture is stirred for one hour at room temperature and
concentrated under vacuum. The resultant crude product is
chromatographed on silica gel, thus obtaining 1.9 g of
6.alpha.-hydroxymethyl-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-
pregn-4-ene-21,17-carbolactone, mp 246.9.degree. C.
(c) A solution of 2.06 g of
6.alpha.-hydroxymethyl-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-
pregn-4-ene-21,17-carbolactone in 20 ml of pyridine is combined
with 3.14 g of p-toluenesulfonic acid chloride; the mixture is
stirred for 3 hours at room temperature, combined with 0.2 ml of
water, agitated for another hour, and the reaction solution is
precipitated into ice water. The resultant precipitate is filtered
off, washed with water, and dried, yielding 2.39 g of
15.beta.,16.beta.-methylene-3-oxo-6.alpha.-tosyloxymethyl-19-nor-17.alpha.
-pregn-4-ene-21,17-carbolactone.
(d) A solution of 3.84 g of trimethylsulfoxonium iodide in 75 ml of
dimethyl sulfoxide is combined with 566 mg of 55% strength sodium
hydride and agitated for one hour at room temperature. To this
solution is added dropwise 2.36 g of
15.beta.,16.beta.-methylene-3-oxo-6.alpha.-tosyloxymethyl-19-nor-17.alpha.
-pregn-4-ene-21,17-carbolactone in 2 ml of dimethyl sulfoxide; the
mixture is agitated for 30 minutes and precipitated into ice water.
The resultant crude product is chromatographed on silica gel, thus
producing 985 mg of
6,6-ethylene-15.beta.,16.beta.-methylene-3-oxo-19-nor-17.alpha.-pregn-4-en
e-21,17-carbolactone, mp 211.degree.-214.degree. C.
The starting compound according to 6(aa) is prepared as
follows:
A solution of 69.2 g of 15.alpha.-hydroxy-4-estrene-3,17-dione in
408 ml of pyridine is combined under ice cooling with 46.4 ml of
benzoyl chloride and stirred for one hour under cooling. Then the
mixture is combined with 5.7 ml of water and agitated for 3 hours
at room temperature and precipitated into ice water. The
thus-formed precipitate is filtered off, washed with water, and
dried, thus yielding 98.7 g of
15.alpha.-benzoyloxy-4-estrene-3,17-dione.
A solution of 98.7 g of 15.alpha.-benzoyloxy-4-estrene-3,17-dione
in 4.5 l of dichloromethane is combined at 0.degree. C. with 266.7
ml of ethylene glycol, 177.8 ml of orthoformic acid triethyl ester,
and 889 mg of p-toluenesulfonic acid and agitated for 2.5 hours at
this temperature. Thereafter the mixture is combined with some
pyridine and washed repeatedly with water. After drying over
magnesium sulfate, the mixture is concentrated under vacuum. The
thus-obtained crude product is chromatographed on silica gel,
yielding 69.1 g of 15.alpha.-benzoyloxy-3,3-ethylenedioxy-5- or
-5(10)-estren-17-one.
A solution of 47.0 g of trimethylsulfoxonium iodide in 1 liter of
dimethyl sulfoxide is combined with 18.4 g of 55% sodium hydride
and agitated for one hour under argon. A solution of 69.1 g of
15.alpha.-benzoyloxy-3,3-ethylenedioxy-5- or -5(10)-estren-17-one
is added dropwise thereto, and the mixture is further stirred at
room temperature for one hour. Subsequently the reaction solution
is stirred into ice water, the resultant precipitate is filtered
off and dried. The thus-obtained crude product is chromatographed
on aluminum oxide, yielding 41.5 g of
3,3-ethylenedioxy-15.beta.,16.beta.-methylene-5- or
-5(10)-estren-17-one as an oil.
A solution of 41.5 g of
3,3-ethylenedioxy-15.beta.,16.beta.-methylene-5- or
-5(10)-estren-17-one in 800 ml of tetrahydrofuran is combined at
0.degree. C. under argon with 148 g of potassium ethylate and then
with a solution of 57 ml of propargyl alcohol in 57 ml of
tetrahydrofuran and further agitated for 2.5 hours at room
temperature. Then the mixture is acidified with sulfuric acid,
diluted with water, extracted with ethyl acetate, and washed
neutral with water. After drying and concentration under vacuum,
the residue is chromatographed on silica gel, thus producing 38.0 g
of
17.beta.-hydroxy-17.alpha.-(3-hydroxy-1-propynyl)-15.beta.,16.beta.-methyl
ene-4-estren-3-one, mp 161.3.degree. C.
A solution of 38.0 g of
17.beta.-hydroxy-17.alpha.-(3-hydroxy-1-propynyl)-15.beta.,16.beta.-methyl
ene-4-estren-3-one in 1 liter of tetrahydrofuran is hydrogenated
with 5.0 g of tris-triphenylphosphine rhodium(I) chloride and then
concentrated under vacuum. Yield: 43.0 g of
17.beta.-hydroxy-17.alpha.-(3-hydroxypropyl)-15.beta.,16.beta.-methylene-4
-estren-3-one.
A solution of 43.0 g of
17.beta.-hydroxy-17.alpha.-(3-hydroxypropyl)-15.beta.,16.beta.-methylene-4
-estren-3-one in 1.4 g of dimethylformamide is combined with 160 g
of pyridine dichromate and stirred overnight at room temperature.
The reaction solution is subsequently stirred into 7 l of ethyl
acetate, suctioned off from the precipitated chromium salts, and
the filtrate is washed with water. After evaporation, the residue
is chromatographed on silica gel, thus obtaining 22.5 g of
15.beta.,16.beta.-methylene-19-nor-3-oxo-17.alpha.-pregn-4-ene-21,17-carbo
lactone, mp 191.2.degree. C.
EXAMPLE OF THE COMPOSITION OF A CONTRACEPTIVE TO BE ADMINISTERED
ORALLY IN THE FORM OF A DRAGEE
______________________________________ Core: 2.000 mg
6,6-Ethylene-15.beta.,16.beta.-methylene-
3-oxo-17.alpha.-pregn-4-ene-21,17- carbolactone 0.050 mg
Ethynylestradiol 31.100 mg Lactose 18.000 mg Corn starch 2.100 mg
Poly-N--vinylpyrrolidone 1.650 mg Talc 0.100 mg Magnesium stearate
55.000 mg Total weight, which is filled up to about 90 mg with the
usual sucrose mixture (coat)
______________________________________
PHARMACOLOGICAL OBSERVATIONS
The antialdosterone activity is determined and measured in the test
odel by Hollmann (G. Hollmann et al., "Tubulaere Wirkungen und
renale Elimination von Spironolactonen" [Tubular Effects and Renal
Elimination of Spironolactones], Naunyn-Schmiedebergs Arch. Exp.
Path. Pharmak. 247: 419 [1964]; P. Marx, "Renale Wirkungen des
d-Aldosterons und seines Antagonisten Spironolacton" [Renal Effects
of d-Aldosterone and Its Antagonist Spironolactone], Diss. Med.
Fak. FU Berlin, 1966).
The results of gestagen activity are obtained in the Caluberg test
with subcutaneous administration of the active agents to castrated
female rabbits. In the histological sections, the secretory
conversion of the endometrium is determined. Evaluation is
performed according to the McPhail scale (evaluation grades 1-4;
1=no conversion; 4=complete conversion).
In the pregnancy maintaining test on rats, the number of living and
dead fetuses is determined after subcutaneous administration of the
test compounds from the 8th to 21st day of gravidity, and the
percentage of pregnancies maintained is calculated.
As can be seen from the table below, the compounds of this
invention 2 and 3 show, with a good aldosterone-antagonistic
activity, a stronger gestagen potency than the comparison compound
1.
__________________________________________________________________________
Antialdosterone Pregnancy Test Clauberg Test Maintaining p.o. s.c.
Test (Spironolactone = Dose McPhail s.c. No. Compound 1) [mg] Value
Dose [mg] %
__________________________________________________________________________
1 6.beta.,7.beta.;15.beta.,16.beta.-Dimethylene- 5-7 1 3.2 3 85
3-oxo-17.alpha.-pregn-4-ene-21,17- 0.3 2.1 1 74 carbolactone
(Comparison) 0.1 1.1 0.3 3 0.1 0 2 6,6-Ethylene-15.beta.,16.beta.-
5 0.3 2.9 0.1 60 methylene-3-oxo-17.alpha.-pregn-4- 0.1 2.6 0.03 11
ene-21,17-carbolactone 0.03 1.3 0.01 0 3
6,6-Ethylene-15.beta.,16.beta.- 1 0.3 2.8
methylene-3-oxo-19-nor-17.alpha.- pregn-4-ene-21,17- carbolactone
__________________________________________________________________________
The preceding examples can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *